IOA Pilot Research Grantees 2010
Once again this year, thanks to the generous support of The Bingham Trust, the IOA was able to award 8 full Pilot Research Grants in support of aging and aging-related disease research. Congratulations to this year's awardees.
This year's Pilot Research Grant Awardees are as follows:
Carlo Ballatore, PhD, Penn School of Medicine
Joseph A. Baur, PhD, Penn School of Medicine
Eric J. Brown, PhD, Penn School of Medicine
Aureo De Paula, PhD, Penn School of Arts and Sciences
Ravishankar Jayadevappa, PhD, Penn School of Medicine
Yuko Kimura, PhD, Penn School of Medicine
Ling Qin, PhD, Penn School of Medicine
John H. Wolfe, VMD, PhD, Penn School of Veterinary Medicine
- Carlo Ballatore, PhD
"Investigation of Structure-Activity Relationship of Noverl 2-Aminobenzothiazoles Inhibitors of Tau Fibril Formation"
The research plan presented in the IOA Pilot Grant proposal entitled “Investigation of Structure-Activity Relationship (SAR) of Novel Inhibitors of Tau Fibril Formation” is focused on SAR elucidation as well as optimization of a novel class of small-molecule inhibitors of tau aggregation that exhibit promising combination of biological activity as well as drug-like physical-chemical properties. These medicinal chemistry efforts will provide data to support a R01 grant proposal aimed at developing agents for in vivo efficacy studies in transgenic animal model of tauopathy to test the hypothesis that compounds capable of slowing/preventing the formation of tau aggregates can delay significantly the onset and/or progression of neurodegeneration.
- Joseph A. Baur, PhD
"Mitochondria as Mediators of the Protective Effects of Caloric Restriction"
Age is the most important risk factor for conditions associated with morbidity and mortality in Western societies, including cancer, cardiovascular disease, and neurodegenerative disorders. Restricting energy intake while maintaining adequate nutrition (caloric restriction, CR) improves health and delays or prevents the onset of age-related diseases. In laboratory rodents, this results in a 20-50% increase in mean lifespan. There is currently no consensus as to how CR works, however a recent observation may help to unravel the mystery. Several treatments that increase lifespan, including CR, have intriguingly been shown to boost the number of mitochondria, the tiny organelles responsible for converting fat, carbohydrates, and proteins into usable energy. Since the effect is common to several lifespan-extending treatments, the signals that trigger an increase in mitochondrial number, or the mitochondria themselves, may play a key role in longevity. Cells in a dish can be induced to make more mitochondria simply by exposing them to serum from calorie-restricted animals, suggesting that it will be possible to study these signaling pathways and assess the effects of “extra” mitochondria on cellular physiology prior to initiating studies on animals. If some of the protective effects of CR can be attributed to changes in mitochondria, this work may offer new opportunities for therapeutic interventions to slow the onset and development of age-related diseases.
- Eric J. Brown, PhD
"A Critical Role for p53 in Facilitating Tissue Regeneration and Suppressing Age-Related Diseases"
Mammalian aging is characterized by a steady decline in tissue regenerative potential. Accumulation of DNA damage in the stem cells that maintain these tissues contributes to this gradual loss. Recent research into factors that influence the ability of stem cells to contribute to tissue homeostasis have focused predominantly on genes that affect their long-term potential. We propose to investigate a less explored paradigm, the role of efficient cellular clearance of terminally damaged cells as a significant contributor to tissue regeneration. To do so, we are utilizing conditional deletion of an important genome maintenance regulator (ATR). Our preliminary evidence indicates that p53, a protein with integral roles in DNA damage-induced cellular clearance, is required for immediate tissue reconstitution after ATR deletion. Importantly, the regenerative failures observed in ATR/p53-deleted mice are associated with the persistence of terminally damaged cells that are unable to contribute productively to tissue function or renewal. We propose to explore the hypothesis that persistence of these damaged cells, both within the stem cell niche and in downstream differentiated progeny, poses a significant barrier to tissue homeostasis and leads to age-related pathologies. These proposed studies will further define p53’s function in tissue renewal following catastrophic replication-associated DNA damage and may demonstrate a pivotal role for damaged-cell clearance in countering premature aging.
- Aureo De Paula, PhD
"Overconfidence and Decision Making in Aging"
Aging is associated with numerous threats to independence and well-being, including loss of cognitive and physical functions. In face of these challenges, older persons frequently are called upon to make financial and other decisions that will directly impact their ability to live independently in the community. The pilot study I propose capitalizes on and supplements a unique longitudinal clinical-pathologic study of aging conducted by the Rush Memory and Aging Project (R01AG17917, PI: Dr. David Bennett). The study is motivated by recent theoretical findings in economics suggesting that lack of recognition of memory loss (as opposed to memory loss itself) is an important factor in the formation of overconfidence. Since many studies indicate that overconfidence is a leading cause of impaired decisions, the above studies suggest a potential link between lack of memory loss recognition and faulty decisions. In collaboration with Drs. David Bennett and Patricia Boyle, leading researchers with the Rush Memory and Aging Project, and Alvaro Sandroni, a renowned economic theorist, I will develop, refine and collect measures of overconfidence, lack of memory loss recognition and study their relation to decision-making by older individuals. We will collect data for a subset of approximately 300 older participants without dementia from the Memory and Aging Project. This empirical analysis will not only allow the testing of the theoretical results mentioned above, but will also help the development of novel theoretical models of behavior relating aging with quality of decisions to further aid empirical and policy work on aging.
- Ravishankar Jayadevappa, PhD
"Behavioral Treatment for Prostate Cancer Care"
The incidence of prostate cancer increases with age and is an important cause of disability in the elderly. Stress is a critical behavioral and environmental factor implicated in the pathogenesis and progression of prostate cancer. Psychosocial stress and related problems contribute to disease burden and impaired health related quality of life (HRQoL) in the elderly. Since prostate cancer affects physical, psychological and interpersonal realms, the associated emotional and cognitive burden can increase stress. Our study conceptual model is based on the psychoneuroimmunology theory. The objective of this study is to evaluate the efficacy and physiological mechanisms of Transcendental Medication (TM) a mediator in improving functional status, HRQoL, psychological well-being, and health resource utilization in elderly prostate cancer patients with intermediate risk of cancer recurrence and treated with radiation therapy. Our primary hypothesis is that TM will be beneficial as a secondary prevention tool in improving HRQoL and psychological well-being of elderly prostate cancer patients. In this three arm single blinded randomized control trial, we will recruit 30 newly diagnosed elderly (65 years or older) prostate cancer patients from the University of Pennsylvania Health System. Subjects will be randomized to a Transcendental Medication group (n=10), Healthy Eating Education group (n=10) or usual care control group (n=10). All three groups will continue to receive their usual treatment. We will collect demographic, clinical, cost and HRQoL data at baseline and at three and six months of follow-up and compare the three groups on objective and subjective parameters. Comparisons will be made on the following outcomes: functional status, physiologic stress, perceived stress, HRQoL, sleep quality, depression, anxiety, distress, and cost of care. With the aging of the U.S. population and earlier diagnoses patterns, the number of men living longer with prostate cancer and its treatment associated morbidities is increase significantly. The complementary alternative medicine based behavioral intervention, Transcendental Medication (TM) has the potential to act as a disease moderator to reduce stress and thereby lead to improved outcomes for elderly prostate cancer patients. This proposed study is a logical next step for our prior prostate cancer outcomes research and will aid in improving the care and outcomes for elderly prostate cancer.
- Yuko Kimura, PhD
"Role of Properdin and Complement Activation in Alzheimer's Disease"
Alzheimer's disease (AD) is progressive neurological disorder, affecting over 5 million people in the USA. It is now recognized that inflammation plays a role in the pathogenesis of AD, but how inflammation is initiated in this condition is not well understood. In this project, we will study the possible role of a protein in the blood, called properdin, in AD and explore if properdin can be exploited as a therapeutic target in AD. Properdin is normally involved in initiating an immune response called complement to defend the host from pathogen infection. However, under certain conditions, properdin may initiate abnormal immune response against self tissues. We recently obtained evidence to suggest that b-amyloid, the abnormal protein deposit commonly found in the brains of AD patients can trigger properdin-dependent complement activation. This project will extend our recent studies and determine in animal models if properdin plays a critical role in AD and whether blocking properdin function might be therapeutically beneficial.
- Ling Qin, PhD
" Osteoblastic Epidermal Growth Factor Receptor Signaling and Osteoporosis"
Osteoporosis is a silent disease due to the imbalance of bone resorption and bone formation. It makes bone prone to fracture and occurs mostly in the aging population. Today, it is a major public health threat for an estimated 44 million Americans, or 55 percent of the people over age of 50. In the past several years, researches in our laboratory and others revealed that epidermal growth factor receptor (EGFR) and its growth factor ligands strongly influence bone metabolism in multiple ways by regulating both osteoblasts, the bone forming cells, and osteoclasts, the bone destroying cells. Our recent preliminary data suggest that lack of EGFR signaling in bone results in bone loss in mice. We hypothesize that osteoblastic EGFR signaling plays a vital role in normal bone metabolism and therefore deficiency in EGFR activity results in osteoporosis. In this project we will develop two animal models to study the physiological roles of EGFR in bone in both adult and old mice. These studies should exploit the possibility whether EGFR could be used as a therapeutic target for treatment of osteoporosis, an aging-related disease.
- John H. Wolfe, VMD, PhD
"iPSCs and NSCs from Alzheimer's Disease Patients"
Our understanding of what is wrong in the brain in Alzheimer’s Disease (AD) has been limited by the inability to obtain live brain cells from patients for study. It has recently become possible to reprogram skin cells from individual patients into stem cells, which can form all types of human tissues. The reprogrammed cells (called induced pluripotent stem cells, iPS cells) can be differentiated into mature cells of specific organs, including brain cells. The iPS cells have potential uses for therapy but also open new avenues to study the mechanisms of human disease. The iPS cells will be converted into brain cells from AD patients and their unaffected family members. We will examine the human genome program characteristic of brain cells to look for AD-specific changes that may implicate specific cellular process in the disease.